Genetic Basis of Cancer

Andrew Read
Dept of Medical Genetics

PowerPoint for lecture, 1500 Monday 6th December 2004

The bad news…..

You are absolutely inevitably all going to get

cancer ….

(unless something else gets you first)

Page 1
1
Page 2
2
Page 3
3
Page 4
4
 The argument from natural selection

Applies equally well to the population of cells that make up a

multicellular organism as it does to a population of whole
organisms

Multicellular organisms are formed by repeated mitosis,

so every cell contains the same genes and DNA

Mutations happen to somatic cell DNA just as much as to germ

line DNA

Inherited vs. somatic genetic

disease

Exactly the same mutations can occur in germ line or somatic

cells, but the observed spectrum is different because:

• many mutations seen in somatic cells would be lethal

if constitutional (e.g. trisomy 8)

• most inherited mutations would have no observable

consequences if present in a small number of somatic cells

Page 5
5
 Inherited vs. somatic genetic
disease

Somatic mutations can be clinically significant when:

• they occur early in embryogenesis, so that the person

ends up with a significant clone of mutant cells
(e.g. mosaic Down syndrome, Duchenne dystrophy etc.)

• they give the cell a growth advantage so that it forms a

tumour
Cancer is the major somatic genetic disease

The natural selection argument

• Cell proliferation is under genetic control

• Mutations will inevitably arise that give a cell a

proliferative advantage

• The daughters of that cell will take over the organism

• Cancer is the natural and inevitable end-state of

all multicellular organisms

Page 6
6
 Natural selection and cancer:
two competing forces

Evolution within an organism

.Resist. Timescale 75 years Develop

Evolution within a species

cancer Timescale 1,000,000,000 years

cancer

The good news…..

It’s statistically impossible for anybody ever

to get cancer

Page 7
7
 Mutation and selection in the
development of tumours

• Age-of-onset data suggest the common epithelial

cancers require 4-7 successive events to convert a
normal epithelial cell into a malignant tumour cell

• i.e. 4-7 independent defences must be knocked out

• If typical mutation rates are 10-6 per cell generation,

the chance of this happening to any of the 1013 cells
in a person is 10-11 - 10-29

So how do we get cancer?

Successful carcinogenesis requires

• Either mutations that increase the rate of cell

proliferation, so as to provide an expanded target for
subsequent mutations

• Or mutations that destabilise the genome, so as to

increase the subsequent mutation rate

Page 8
8
 General features of cancer: clonal
evolution

Implications of clonal evolution of cancers

• Multistage process with each stage driven by genetic changes
– some stages may be clinically or histologically identifiable
– genetic changes precede morphological changes thus may
serve as early markers

• Occurs over a relatively long period - early intervention

may be possible

Page 9
9
 Implications of genomic instability

• Very complex genotypes in cancer:

grossly abnormal karyotypes
many genes mutated, deleted or amplified

• Cancers may consist of multiple clones with

different genetic lesions

• Corrective gene therapy for common cancers unlikely

Genes involved in tumorigenesis

• Oncogenes:
Genes that gain function in cancer development
Dominant (one copy of the gene needs to be activated)
“Accelerator” - normal function favours cell proliferation

• Tumour Suppressor Genes:

Genes that sustain loss of function in cancer development

Recessive (both copies need to be inactivated)

“Brakes” - normal function restrains cell proliferation

Page 10
10
 Functions of Oncogenes

• Secreted growth factors PDGF

• Cell surface receptors ERBB, RET, MET

• Signal transduction system components RAS, ABL

• Nuclear proteins, transcription factors MYC, JUN

• Cyclins/Cyclin-dependent kinases CYCLIN D1, CDK

Functions of Tumour Suppressor Genes

• DNA-binding transcription factors (p53, WT1)

• Transcriptional regulators (Rb, APC, ?BRCA1)

• Signal transduction system components (NF1, p16, DPC4, Patched)

• Phosphatases (PTEN)

• DNA repair and genome stability (p53, BRCA1 & BRCA2)

• Structural protein (NF2)

Page 11
11
 Cancer: the six capabilities
A successful cancer cell must:
• become independent of external growth signals
• become insensitive to external anti-growth signals

• become able to avoid apoptosis

• become capable of indefinite replication

• become capable of sustained angiogenesis

• become capable of tissue invasion and metastasis

Hanahan & Weinberg Cell 100 57-70 ; 2000

Activation of oncogenes

• By point mutation

Page 12
12
Activation of RET oncogene by point mutation

GDNF

Mutation
TM
Cyto
RET
receptor tyrosine kinase

Signalling Signalling

Activation of oncogenes

• By point mutation

• By amplification

• By chromosomal translocation that up-regulates

expression

Page 13
13
 Activation of MYC oncogene by an
8:14 translocation

Result is Burkitt’s lymphoma

Activation of oncogenes

• By point mutation

• By amplification

• By chromosomal translocation that up-regulates

expression

• By chromosomal translocation that creates a novel

chimaeric gene

Page 14
14
 Activation of ABL oncogene by a
9:22 translocation
Result is a novel chimaeric
gene

Gene encodes an over-active

growth signalling molecule

Causes chronic myeloid

leukaemia

Gleevec is a specific
inhibitor of the novel kinase

Inactivation of tumour suppressor

genes

• By point mutation (missense, nonsense, frameshift… )

• By deletion of all or part of the gene

• By loss of all or part of the relevant chromosome

• By silencing a structurally intact gene by methylation of

the DNA of its promoter

Page 15
15
 Familial vs. sporadic cancers

99% of cancers are sporadic, no inherited susceptibility

1% involve inherited susceptibility :

• manifest as rare mendelian dominant syndromes

• increased cancer susceptibility

• may be associated with multiple tumour types

• may be associated with other abnormalities

Risk of Neoplasia in Cancer Syndromes

Syndrome Neoplasia Lifetime risk (%)

NF1 Plexiform neurofibroma <4
Optic glioma <15
FAP Bowel cancer 100
VHL Cerebellar H'angioblastoma 84
Retinal angioma 70
Renal cell carcinoma 69
AT Lymphoma 60
Leukaemia 27
MEN2A Medullary thryoid carcinoma NA
Phaechromocytoma 50
Melanoma Melanoma 65
BRCA1 Breast 85
Ovary 63
Colon 4.1*
Prostate 3.3*
HNPCC Colon and endometrium 75-90

Page 16
16
 Knudson’s two-hit hypothesis

• The same genetic changes cause the common sporadic

and rare familial forms of the disease

• Oncogenesis requires two successive mutations in one cell

• In the familial form the first hit is inherited, the

second is acquired

• The familial condition is dominant at the pedigree

level but recessive at the cell level

Inactivation of Tumour Suppressor

Genes in familial cancers
• First ‘hit’
– (mutation of one copy of the gene)
– occurs in the GERMLINE

• Second ‘hit’
– (mutation of the second copy of the gene)
– occurs in the SOMATIC cells

Page 17
17
Germ cell Somatic cells

1st
HIT
2nd
Tumour cells HIT

Inactivation of Tumour Suppressor Genes

in sporadic cancers

• First ‘hit’
– (mutation or loss of one copy of the gene)
– occurs in a SOMATIC cell

• Second ‘hit’
– (mutation or loss of the second copy of the gene)
– occurs in the SOMATIC cell carrying the first hit
or in one of its descendants

Page 18
18
 Somatic cells Somatic cells

1st
HIT

2nd
Tumour cells HIT

Tumour Suppressor Genes

• Familial Cancer: • Sporadic Cancer:

– Early onset – Later onset
– Multiple tumours of same – Single tumour usually
type
– Other tumours – No other tumours usually
– Tumour cells have both – Tumour cells have both
copies of TSG inactivated copies of TSG inactivated
– All other cells one copy of – All other cells normal
TSG inactivated

Page 19
19
 2-hit hypothesis for retinoblastoma

Suppose there are 107 target cells and the chance of a mutation
happening to a given cell is 1 in 106
The incidence of sporadic retinoblastoma will be 107 x10-6x10-6
The risk of retinoblastoma in somebody inheriting one mutation
will be 107 x10-6 i.e familial Rb has a high penetrance

Retinoblastoma as model of
Knudson’s two hit hypothesis

• Familial form: • Sporadic form:

– Onset: <2yrs – Onset: 4-5th year
– Bilateral – Unilateral
– Osteosarcomas – No other tumours
– Tumour cells both copies of – Tumour cells both copies of
Rb inactivated Rb inactivated
– All other cells one copy of – All other cells normal
Rb inactivated

Page 20
20
 Colorectal cancer

• Conversion to malignancy occurs in a multistage

process

• Stages recognisable as distinct entities

Normal epithelium

Aberrant dysplastic crypt focus

Early adenoma
Intermediate adenoma

Late adenoma

Carcinoma

Metastases

Page 21
21
 Familial Adenomatous Polyposis

• Inheritance: Autosomal Dominant

• Gene: APC

• Incidence: ~1 : 8000 - 10000

• Features: Colonic and Extracolonic

Familial Adenomatous Polyposis

Colon:

Many polyps (adenomas)

develop, usually after
puberty

One or more polyps

transform to
adenocarcinoma, usually
in 3rd / 4th decades.

Page 22
22
 Familial Adenomatous Polyposis

• Extracolonic features
– Dento-osseous changes
– Congenital hypertrophy of retinal pigmentary
epithelium (CHRPE)
– Desmoids
– Sebaceous cysts
– Extracolonic polyposis and carcinoma

Genetic changes in FAP and sporadic

colorectal cancers
• Familial adenomatous polyposis (FAP)
» APC mutation:
• inherited germline mutation of one copy of APC
• somatic mutation of second APC allele
• occurs early in the multistage process
• multiple polyps (adenomas)

Page 23
23
 Genetic changes in FAP and sporadic
colorectal cancers

• Sporadic CRC
» APC mutation:
• somatic mutation of one copy of APC
• somatic mutation of second APC allele in the clone
of cells carrying the first hit
• single polyp (adenoma)

Genetic events in colorectal carcinogenesis

Normal epithelium
APC inactivation x2
Aberrant dysplastic crypt
focus
Alterations in DNA methylation
Early adenoma
KRAS activation x1
Intermediate adenoma
SMAD4 inactivation x2
Late adenoma
TP53 inactivation x2
Carcinoma

Page 24
24
 Genetic changes in FAP and sporadic
colorectal cancers
• Mutation of both oncogenes and TSGs (other than
APC)
– KRAS; TP53, SMAD4

• Sequence of events appears to be important:

– APC : early change - GATEKEEPER
– KRAS : early change
– SMAD4 : intermediate change
– TP53 late change

• Progressive loss of proliferation control

Cancer Genetics- Summary (1)

• All cancers are genetic diseases

– Some cancers are familial diseases
– Most cancers are sporadic diseases

• Carcinogenesis is driven by
– Clonal selection
– Genomic instability

Page 25
25
 Cancer Genetics- Summary (2)

• Two groups of genes involved in cancer

– Oncogenes
– Tumour suppressor genes

• Most common cancers arise through a

multistage process
– Alteration of 4-7 genes necessary
– Both oncogenes and tumour suppressor genes
involved

Cancer Genetics- Summary (3)

Think pathways and capabilities,

not genes !

Page 26
26